Psychological Medicine (2011), 41, 207–216.

f Cambridge University Press 2010 O R I G I N A L AR T I C LE

doi:10.1017/S0033291710000309

Frontostriatal activation in patients with

obsessive–compulsive disorder before
and after cognitive behavioral therapy

T. Freyer1, S. Klöppel1, O. Tüscher2, A. Kordon3, B. Zurowski3, A.-K. Kuelz1, O. Speck4, V. Glauche2

and U. Voderholzer1,5*
1
Department of Psychiatry and Psychotherapy, University Medical Center, Albert-Ludwigs-University Freiburg, Germany
2
Department of Neurology, University Medical Center, Albert-Ludwigs-University Freiburg, Germany
3
Department of Psychiatry and Psychotherapy, University of Luebeck, Germany
4
Department of Biomedical Magnetic Resonance, Institute for Experimental Physics, Otto-von-Guericke-University Magdeburg, Germany
5
Medical-Psychosomatic Hospital Roseneck, Prien, Germany

Background. Cognitive behavioral therapy (CBT) with exposure and response prevention (ERP) is the
psychotherapeutic treatment of choice for obsessive–compulsive disorder (OCD). However, little is known about the
impact of CBT on frontostriatal dysfunctioning, known to be the neuronal correlate of OCD.

Method. A probabilistic reversal learning (RL) task probing adaptive strategy switching capabilities was used in 10
unmedicated patients with OCD and 10 healthy controls during an event-related functional magnetic resonance
imaging (fMRI) experiment. Patients were scanned before and after intensive CBT, controls twice at comparable
intervals.

Results. Strategy change within the RL task involved activity in a broad frontal network in patients and controls. No
significant differences between the groups or in group by time interactions were detected in a whole-brain analysis
corrected for multiple comparisons. However, a reanalysis with a more lenient threshold revealed decreased
responsiveness of the orbitofrontal cortex and right putamen during strategy change before treatment in patients
compared with healthy subjects. A group by time effect was found in the caudate nucleus, demonstrating increased
activity for patients over the course of time. Patients with greater clinical improvement, reflected by greater
reductions in Yale–Brown Obsessive Compulsive Scale (YBOCS) scores, showed more stable activation in the
pallidum.

Conclusions. Although these findings are preliminary and need to be replicated in larger samples, they indicate a
possible influence of psychotherapy on brain activity in core regions that have been shown to be directly involved
both in acquisition of behavioral rules and stereotypes and in the pathophysiology of OCD, the caudate nucleus and
the pallidum.

Received 6 October 2009 ; Revised 1 February 2010 ; Accepted 2 February 2010 ; First published online 18 March 2010

Key words : Cognitive behavioral therapy, frontostriatal dysfunction, functional brain imaging, obsessive–compulsive
disorder.

Introduction OCD is associated with abnormal neuronal func-

tioning in a corticostriatal circuitry mediating inhi-
Obsessive–compulsive disorder (OCD) is a neuropsy-
bitory control and flexible responding. Several studies
chiatric disorder characterized by recurrent intrusive
have demonstrated that patients with OCD exhibit an
thoughts and/or repetitive rituals called compulsions.
increased metabolism during rest conditions pre-
First-line treatments are cognitive behavioral therapy
dominantly in the orbitofrontal cortex and in striatal
(CBT) with exposure and response prevention (ERP)
areas in comparison to healthy controls (Baxter et al.
and pharmacotherapy, with serotonin reuptake
1987 ; Whiteside et al. 2004). However, when cogni-
inhibitors being effective in about 60–70 % of all
tively challenged by decision-making or planning
patients (Foa et al. 2005 ; Abramowitz, 2006).
tasks (van den Heuvel et al. 2005 ; Remijnse et al. 2006 ;
Chamberlain et al. 2008), these patients demonstrated
a reduced responsiveness in the aforementioned areas.
* Address for correspondence : Professor U. Voderholzer, M.D.,
Medical-Psychosomatic Clinic, Roseneck, Germany. Current models of OCD therefore consider an im-
(Email : ulrich.voderholzer@uniklinik-freiburg.de) paired frontostriatal circuitry as a correlate of this

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 208 T. Freyer et al.
disorder. Both Remijnse et al. (2006) and Chamberlain
et al. (2008) used a reversal learning (RL) paradigm
to gain a better understanding of these mechanisms.
RL requires flexible alteration of behavior after nega-
tive feedback and is known to be dependent on
the serotonergic system (Clarke et al. 2007) and also
on the integrity of the orbitofrontal cortex and the
medial striatum (Clarke et al. 2008). Remijnse,
Chamberlain and co-workers demonstrated abnor-
mally reduced activation of orbitofrontal areas on RL
in OCD patients compared with healthy subjects. This
supports the hypothesis of a dysfunctional fronto-
striatal circuitry associated with obsessive–compulsive
symptoms.
To date, few studies have examined the impact of
treatment in general and of psychotherapy in particu-
lar on the neurobiology of OCD (Baxter et al. 1992 ;
Schwartz et al. 1996 ; Ho Pian et al. 2005 ; Nakao et al.
2005 ; Nabeyama et al. 2008). Baxter et al. (1992) dem-
onstrated statistically significant decreases in glucose
metabolic rates in the right head of the caudate
nucleus after effective treatment of OCD with either
pharmacological or behavioral therapy. In a positron
emission tomography (PET) study the same group
replicated these findings specifically for behavioral
therapy and demonstrated a normalization of patho-
logical correlational activity between the orbital cortex
and the caudate nucleus (Schwartz et al. 1996). In line
with these findings, Saxena et al. (1999) found a re-
duction of primarily elevated metabolism in the orbito-
frontal cortex and in the caudate nucleus under
treatment with paroxetine. Using functional magnetic
resonance imaging (fMRI), Nakao et al. (2005) demon-
strated diminished activation in orbitofrontal and
dorsolateral prefrontal areas in the course of treatment
under symptom provocation.
RL includes planning in conjunction with cognitive
flexibility and closely resembles a core cognitive dys-
function of OCD (Chamberlain et al. 2008 ; Valerius
et al. 2008). Therefore, it is possible that severely
affected patients exhibit abnormalities in the neural
correlates of RL and that these abnormalities will
normalize under symptom reduction through psycho-
therapy. The only studies examining the effects of
treatment on brain function in OCD to date used
PET and analyzed metabolism during rest. So far no
study in OCD patients has used higher cognitive
tasks such as RL probing into frontostriatal circuitry
in a longitudinal design. As we have recently demon-
strated the high test–retest reliability of the RL task
(no changes in brain activation of healthy subjects
when tested twice with an interval of several weeks ;
Freyer et al. 2009), we consider it suitable for a longi-
tudinal study aiming to detect changes in the course
of treatment.
https://doi.org/10.1017/S0033291710000309 Published online by Cambridge University Press
In the current study we sought to investigate the
impact of psychotherapy on frontostriatal responsive-
ness using a test challenging cognitive flexibility.
Based on previous work, we expected OCD patients to
show reduced orbitofrontal and striatal activation be-
fore treatment and a subsequent normalization fol-
lowing CBT.
Method
Subjects
Ten right-handed patients with OCD [three females,
mean age 36.1 (S.D.=9.36) years] and 10 healthy con-
trols [four females, mean age 39.6 (S.D.=10.48) years]
participated in this study. All patients were in-patients
being treated in the Department of Psychiatry and
Psychotherapy of the University Hospital Freiburg
throughout the entire study. Patients were character-
ized by the following compulsions and obsessions :
four patients presented with washing compulsions,
two with checking compulsions, one had predomin-
antly obsessive thoughts and three presented with
mixed OCD symptoms. The time interval between
the onset of OCD and study participation was 11.7
(S.D.=5.6) years. Nine patients had no psychiatric co-
morbidities and one patient had a past medical history
of bulimic episodes. In-patient treatment duration
varied from 8 to 12 weeks and was carried out by
two experienced therapists specially trained in CBT
with OCD patients, following a structured concept
(Hohagen et al. 1998). Concomitant psychotropic
medication was an exclusion criterion.
The first treatment phase comprises 6 h of assess-
ment and treatment planning. During this phase, an
individual disease model and information about the
cognitive behavioral concept of OCD are provided.
Thereafter, 16 treatment sessions with ERP lasting
about 90 to 120 min over a period of 4 to 6 weeks were
provided. The therapist accompanied and supervised
the exposure sessions and assigned self-exposure
practice to be completed by the patients between ses-
sions. ERP sessions were in vivo and also included
home sessions.
Measurements using the Hamilton Depression
Rating Scale (HAMD ; Hamilton, 1960), the Yale–
Brown Obsessive Compulsive Scale (YBOCS ;
Goodman et al. 1989) and MRI scanning were con-
ducted during the first week after admission before
starting with the exposure phase and also immediately
before discharge from hospital.
Healthy controls were recruited by personal contact
and newspaper advertisements that did not specify
the disorder under investigation. Controls were
matched for age, sex and education. Personal or family
 Frontostriatal activation in patients with OCD before and after CBT
False
response
Correct
response
Correct
response
Probabilistic
error*
False
response
Fig. 1. Illustration of the reversal learning task : a square and a triangle are presented. Subjects have to select one of these objects
using a right-hand button press. Feedback indicated a right or wrong answer. * Indicates a wrong choice despite a correct
response.
history of a psychiatric disorder or evidence of sub-
clinical obsessions or compulsions led to exclusion.
Subjects were measured twice with an interval com-
parable to the treatment duration of patients.
Exclusion criteria for both patients and healthy
controls were the presence of substantial neurological
impairment, head injury, substance abuse, current or
previous psychotic episodes, pregnancy and age >65
years. All patients were free of psychotropic medi-
cation for at least 4 weeks prior to baseline examin-
ation and throughout the whole treatment until the
second MRI scan. Six patients were naı̈ve for psycho-
tropic medication and four patients had a medication
history of selective serotonin reuptake inhibitors. The
study was approved by the Ethics Committee of the
University of Freiburg according to the guidelines of
the Declaration of Helsinki. Informed written consent
was obtained from each subject. The study was con-
ducted in the Department of Diagnostic Radiology at
the University Hospital Freiburg.
Procedures
Stimuli and task design (Fig. 1)
Details of the RL task used have been published pre-
viously (Valerius et al. 2008). In brief, subjects were
asked to choose one of two simultaneously presented
abstract patterns (a square and a triangle) in each trial
by pressing a right or left button on a button box
positioned on the abdomen of the subject. A feedback
in the form of a green happy face or a sad red
face pictogram was presented immediately after the
choice, indicating whether the answer was correct
or incorrect. After 10 to 15 (randomized) correct
https://doi.org/10.1017/S0033291710000309 Published online by Cambridge University Press
209
Correct
response
responses, the target object changed and subjects
had to adapt their strategy by selecting the previously
incorrect stimulus. As an additional challenge, prob-
abilistic errors were interspersed, leading to negative
feedback despite a correct response in respect of the
current rule. If subjects changed their strategy after
a probabilistic error, this was counted as a mistake
(SCAPE=strategy change after a probabilistic error).
Subjects were asked to respond as rapidly as possible
without compromising accuracy.
Two successive 9-min runs within one scanning
session, each with 10 rule changes (hence nine reversal
stages), were presented. Each discrimination phase
contained between zero and four probabilistic errors.
Objects appeared for a maximum of 2 s, limited by
subjects’ responses. Feedback was presented immedi-
ately after subject responses for 0.5 s, followed by a
fixation cross for a minimum of 0.8 s, leading to an
interstimulus interval of 3.3 s.
The task was programmed using ‘ Presentation ’
software (www.neurobehaviouralsystems.com) and
was projected onto a screen behind the subject, viewed
via a mirror mounted on the head coil. Before entering
the scanner, subjects performed a 30-trial training
session on a standard desktop PC. This was a simple
probabilistic discrimination task (i.e. without reversal
stages) designed to introduce the subject to the con-
cept of a probabilistic error without the need to reverse
responding.
Data acquisition
MRI was performed on a Siemens Trio 3-T scanner
(Siemens AG, Germany). Functional MR images were
 210 T. Freyer et al.
acquired using gradient-echo echo-planar imaging
(GE-EPI) sequences sensitive to blood oxygen level-
dependent (BOLD) contrast [repetition time (TR)=
3000 ms, echo time (TE)=30 ms, flip angle=90x, field
of view (FOV)=256 mm, matrix=128r120, 32 inter-
leaved slices, 3 mm slice thickness]. The event-related
design included 400 acquisitions, of which the first five
images were discarded to eliminate magnetization in-
stability. Patients were hospitalized for CBT and per-
formed a scanning session with two runs before and
after therapy [average interval 57 (S.D.=17.8) days].
Control subjects performed two identical sessions
[average interval 119 (S.D.=84.4) days]. The interval
tended to be longer in the control group, but not sig-
nificantly so (p=0.07). The study setting and the per-
forming physician (T.F.) were identical in both
sessions to control for possible confounds.
High-resolution anatomical images were acquired
using a sagittal T1-weighted 3D-MPRAGE sequence
[TR=2200 ms, inversion time (TI)=1100 ms, TE=
4.91 ms, flip angle=12x, FOV=256 mm, matrix=
256r256, 160 slices, voxel size=1r1r1 mm3] to ex-
clude structural abnormalities and to aid in spatial
normalization.
Data analysis and image processing
Behavioral data were analyzed in SPSS version 15.0
(www.spss.com). Parameters for task performance
were reaction times and error numbers, clinical status
was quantified by HAMD and YBOCS scores.
Kolmogorov–Smirnov testing did not reject the as-
sumption of normal distribution for any of the vari-
ables. Paired t tests were used to evaluate differences
between the sessions. Two-sample t tests served to
compare differences between patients and controls
separately for each session.
Imaging data analysis was performed using SPM5
(www.fil.ion.ucl.ac.uk/spm) running under MATLAB
7.1 (www.mathworks.com). Images were corrected for
slice acquisition delay, spatially co-registered to the
individual T1 image and normalized onto the
Montreal Neurologic Institute (MNI) Atlas using nor-
malization parameters estimated from the anatomical
image. Finally, functional data were smoothed with an
isotropic 8-mm full-width at half-maximum (FWHM)
Gaussian kernel.
A first-level analysis based on the general linear
model (Friston et al. 1995) was performed for each
subject individually. Task-related changes in fMRI
signal were estimated at each voxel by modeling the
onsets of the responses as stick functions with a hemo-
dynamic response function. The time series were high-
pass filtered with a cut-off at 128 s. Six movement
parameters (x, y, z, pitch, roll, yaw) resulting from the
https://doi.org/10.1017/S0033291710000309 Published online by Cambridge University Press
image realignment were modeled as additional re-
gressors to control for movement artifacts. Onsets co-
occurred with the presentation of the feedback. We
sought to model all possible event types with separate
regressors to reduce heterogeneity of neuronal pro-
cessing in the regressor of interest (i.e. the last reversal
error). The following events were modeled : (1) first
correct responses following a response shift ; (2) spon-
taneous errors ; (3) probabilistic errors, on which nega-
tive feedback was given to correct responses ; (4)
SCAPES ; (5) reversal errors ; and (6) last reversal
errors, resulting in the subject shifting the response
strategy. Correct responses co-occurring with positive
feedback were defined as baseline trials. We did not
include first correct responses in the baseline con-
dition because we expected neuronal processing
specific to successful strategy change. The last reversal
error before strategy change was chosen as the critical
event of interest (i.e. reflecting RL) because activation
of a reversal network was assumed to specifically fol-
low this last negative feedback. Therefore, parameter
estimates reflecting activations with last reversal error
compared to implicit (unmodeled) baseline were
computed and constituted a statistical parametric map
for each individual, which then entered a second-level
analysis.
The parameter images of the first session (effect of
last reversal error compared to baseline of patients
and controls) were first entered into a second-level
(random effects) analysis by calculating a one-sample
t test to determine the overall effect of strategy change.
An additional simple correlation model was used to
identify brain regions showing a linear change with
the YBOCS score. A two-factor ANOVA with time
point (session 1 and session 2) as the within-subject
factor and group (patients versus controls) as the
between-subjects factor was computed to test for an
interaction representing treatment-specific effects over
time. A final model was set up to identify those areas
co-varying with the change in the YBOCS score over
the course of the treatment. To this end, we subtracted
the parameter image from the first session from that of
the second session separately for each patient. The
same was done for the YBOCS scores. We then corre-
lated the change in the parameter estimates with that
of the YBOCS scores. Based on earlier work, we ex-
pected a clinical improvement (i.e. a reduction in the
YBOCS score) to be paralleled by increasing activa-
tions in the striatum.
Effects are reported after correction for multiple
comparisons using the false discovery rate (FDR) as
implemented in SPM5 across the whole brain with
p<0.01 at the voxel level. Based on our anatomical a
priori hypotheses, we additionally report effects within
the frontal cortex and the striatum with p<0.001
 Frontostriatal activation in patients with OCD before and after CBT 211

uncorrected (Gottfried et al. 2004). Coordinates are Table 1. Demographics and clinical data
given in MNI space.
Patients Controls

Results Age (years) 36.1 (9.36) 39.6 (10.48)

Behavioral data
Table 1 summarizes the clinical characteristics of the
patients, and Table 2 shows the behavioral data for the
patients and controls from the RL task. No significant
differences overall in error rates or reaction times were
found between patients and controls. However, in the
patient group before therapy there was a negative
correlation between the number of spontaneous errors
and the YBOCS scores (YBOCS total, r=x0.78, p=
0.004 ; YBOCS obsessions, r=x0.78, p=0.004 ; YBOCS
compulsions, r=x0.70, p=0.013) and a negative cor-
relation, nearing significance, between the number of
SCAPES, representing unnecessary strategy changes
after a probabilistic error, and the YBOCS obsessions
scores (r=x0.53, p=0.06).
Following treatment, mean total YBOCS scores
decreased significantly from 25.4 to 14.2 (p=0.002 ;
one-tailed paired t test). Similarly, significant im-
provements were found for the YBOCS subscores for
obsessions and compulsions. Using a 35 % reduction
of the total YBOCS scores as the criterion, seven out of
10 patients responded to CBT. The correlations be-
tween YBOCS scores and the number of spontaneous
errors and the number of SCAPES were no longer de-
tected after treatment.
Imaging data
Regions activated during strategy change (last reversal
error minus baseline events) across all subjects are
shown in Fig. 2. Pooled across both groups, a task-
specific BOLD response was found in the bilateral in-
sular cortex (coordinates x, y, z=33, 21, x9 ; T=9.82
and coordinates x, y, z=x27, 24, –6 ; T=8.13), dorsal
medial frontal cortex (coordinates x, y, z=3, 18, 54 ;
T=11.56), bilateral parietal cortex (coordinates x, y,
z=x33, x51, 42 ; T=9.10 and coordinates x, y, z=45,
x48, 51 ; T=7.32), bilateral middle frontal cortex (co-
ordinates x, y, z=x30, 48, 18 ; T=6.17 and coordinates
x, y, z=30, 51, 21 ; T=7.44) and right orbitofrontal
cortex (coordinates x, y, z=24, 42, x15 ; T=4.63).
Neither significant differences between the groups
nor significant time by group interactions were found
on a corrected level. However, the reanalysis with
more lenient thresholds (p<0.001 uncorrected) re-
vealed the following findings within the a priori
regions. Before the start of psychotherapy, reduced
activations in patients compared with controls in the
bilateral orbitofrontal cortex (coordinates x, y, z=
Sex (female : male) 3:7 3:7
Duration of school education 1:3:6 1:3:6
(9 years : 10 years : 13 years)
Session 1 Session 2 p value
YBOCS 25.4 (4.81) 14.2 (6.18) 0.003
YBOCS obsessions 12.5 (2.76) 7.2 (3.26) 0.004
YBOCS compulsions 12.9 (2.28) 7.0 (3.30) 0.003
HAMD 6.3 (5.48) 4.7 (5.10) 0.36
YBOCS, Yale–Brown Obsessive Compulsive Scale ;
HAMD, Hamilton Depression Rating Scale.
Values are given as mean (standard deviation). p values are
derived from paired t tests.
x21, 42, x12 ; T=3.86 and coordinates x, y, z=21, 42,
x9 ; T=3.82) and the right putamen (24, 12, 0 ;
T=3.42) were found (Fig. 3). No areas were found
showing a linear correlation between brain activity
and YBOCS scores within the patient group. After
treatment, the comparison patients/controls still re-
vealed a difference in the right orbitofrontal cortex
(coordinates x, y, z=24, 42, x9 ; T=3.77) but not in the
putamen. Testing for an interaction between group
and time showed differential activations in the
caudate nucleus (coordinates x, y, z=6, 6, 9 ; T=3.63 ;
Fig. 4). Fig. 5 illustrates that this is explained by in-
creasing activations over time in the patient group but
not in the healthy subjects. OCD patients with greater
reductions of the total YBOCS score showed smaller
activation increases in the pallidal region (coordinates
x, y, z=24, 3, 6 ; T=4.72 ; Fig. 6).
Discussion
The presented study provides the first evidence for
functional neuronal changes after CBT in the basal
ganglia as part of the frontostriatal network implicated
in OCD using a disease-pertinent cognitive activation
paradigm. To our knowledge this is the first study
examining effects of psychotherapy on brain function
in non-medicated, non-depressed, severely affected
OCD patients in a longitudinal design with a matched
group of healthy controls. However, these high meth-
odological requirements inevitably lead to small sam-
ples, limiting the statistical power (reflected by a lack
of significant effects corrected for multiple com-
parisons) and the data interpretation and conclusions.
Nevertheless, our preliminary data stress the potential

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 212 T. Freyer et al.

Table 2. Performance in the reversal learning (RL) task

Between-session Between-group
Patients Controls differences, p value differences, p value

Event type Session 1 Session 2 Session 1 Session 2 Patients Controls Session 1 Session 2

Numbers
First correct response 18 (0) 18 (0) 18 (0) 18 (0) 1.00 1.00 1.00 1.00
Spontaneous error 16.8 (7.1) 14.9 (12.9) 25.6 (12.6) 31.8 (25.4) 0.56 0.49 0.07 0.08
Probabilistic error 39.9 (9.2) 40.8 (10.7) 37.3 (6.9) 34.6 (11.6) 0.77 0.45 0.48 0.23
SCAPE 6.1 (4.0) 4.4 (5.0) 4.1 (2.5) 7.1 (5.4) 0.10 0.13 0.19 0.27
Reversal error 23.5 (7.0) 22.6 (8.6) 29.2 (6.1) 23.8 (8.7) 0.60 0.07 0.07 0.76
Last reversal error 18 (0) 18 (0) 18 (0) 18 (0) 1.00 1.00 1.00 1.00
Reaction times (ms)
First correct response 661 (113) 616 (83) 581 (119) 562 (88) 0.16 0.38 0.14 0.18
Spontaneous error 704 (109) 637 (107) 587 (149) 632 (158) 0.08 0.44 0.06 0.94
Probabilistic error 590 (81) 574 (66) 544 (115) 520 (65) 0.48 0.26 0.32 0.08
SCAPE 604 (112) 524 (88) 559 (135) 524 (84) 0.09 0.32 0.41 1.00
Reversal error 594 (73) 592 (77) 539 (111) 538 (112) 0.73 0.74 0.21 0.23
Last reversal error 603 (82) 574 (93) 541 (99) 513 (78) 0.31 0.12 0.15 0.13

SCAPE, Strategy change after a probabilistic error.

Mean values of event numbers and event reaction times are given with the standard deviation in parentheses.
p values of paired t tests are given for between-session differences, p values of two-sample t tests are given for between-group
differences.

Fig. 2. Effect of last reversal error across both groups. Activations are rendered on a template brain in
Montreal Neurologic Institute (MNI) space (p<0.01, false discovery rate-corrected).

neuronal effects of successful CBT and therefore con-
tribute to the understanding of frontostriatal pathol-
ogy in OCD. We also replicate and extend findings
described previously on both the behavioral and the
neuronal level.
As symptoms in all patients had been stable over
several years before inclusion in the study, an im-
provement in YBOCS scores is likely to be the effect of
CBT. Treatment (i.e. CBT in patients) by group analy-
sis showed an interaction in the caudate head. This is
caused by patients showing relatively decreased acti-
vations before CBT but increased activations after re-
ceiving CBT compared to controls (see figures 4 and 5).
The peak location in the frontostriatal circuitry is well
in line with the proposed impairment of this circuitry
in OCD (Huey et al. 2008 ; Maia et al. 2008) and also
with the most consistent findings as suggested by
meta-analyses of neuroimaging studies of OCD
(Whiteside et al. 2004 ; Menzies et al. 2008). However,
previous neuroimaging studies on CBT in OCD con-
sistently reported hyperactivity in the right caudate
before treatment that decreased to normal activity
after therapy compared to control subjects (Baxter et al.
1992 ; Schwartz et al. 1996 ; Nakatani et al. 2003 ; for a
review see Linden, 2006). It should be taken into con-
sideration, however, that these studies investigated

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 Frontostriatal activation in patients with OCD before and after CBT 213

0
z=0 T score z = –12

Fig. 3. Areas showing decreased activations with last reversal error in obsessive–compulsive disorder patients before treatment
compared to controls. Activations are overlaid on a standard brain in Montreal Neurologic Institute (MNI) space (p<0.01,
uncorrected).

0
x = 10 T-score z=9

Fig. 4. Areas showing an interaction between time (i.e. treatment in the obsessive–compulsive disorder group) and group.
Activations are overlaid on a standard brain in Montreal Neurologic Institute (MNI) space (p<0.01, uncorrected).

metabolism or cerebral blood flow in the resting state.

Estimates of neuronal activations at

The hypoactivity before treatment observed in our

x, y, z = 6, 6, 9 in arbitrary units

active task could be due to a lack of modulatory ca-

pacity in the caudate nucleus, meaning that patients’
pathologically elevated caudate activity at baseline
cannot be sufficiently upregulated when challenged
through RL as it is in healthy subjects. This would ex-
plain why the difference between last reversal error
and baseline before treatment was smaller in patients
than in controls. Furthermore, we observed an in-
crease in the activation difference after treatment, Time point 1 Time point 2 Time point 1 Time point 2
suggesting a recovery of modulatory capacity through OCD patients Healthy controls

CBT. Correspondingly, patients with greater clinical
improvement, reflected by greater reductions in
YBOCS scores, showed less increase of activation in
the pallidum, suggesting regained control of caudate
over pallidal activity. Taken together, these anti-
parallel activity changes in the caudate and pallidum
in concert with a normalization of activity in the OFC
under treatment fit well into proposed models of
striato-orbitofrontal pathology of OCD (Huey et al.
2008 ; Menzies et al. 2008). In addition, the results are in
line with striato-orbitofrontal models of RL (Frank &
Claus, 2006).
Fig. 5. Group- and time point-specific estimates of activation
in the caudate head peak voxel found in the interaction
analysis. Error bars indicate 90 % confidence intervals.
The literature on neuropsychological deficits in
OCD is heterogeneous, as are the behavioral results of
studies testing cognitive flexibility of OCD patients
with the RL task. Although Remijnse et al. (2006, 2009)
found differences in task performance, our results
are in line with other work on the identical version of
this task (Valerius et al. 2008) and on variations
(Chamberlain et al. 2008). Differences in neuronal

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 214 T. Freyer et al.

last reversal error in the right

Changes of activations with

pallidum (24, 3, 6) (AU)

6 2.00

0.00
4

–2.00
2

–4.00
0
z=6 0.00 10.00 20.00
Reduction of total YBOCS
score with treatment

Fig. 6. Smaller increases in activation in the right pallidum are associated with larger improvements of the clinical
presentation. Right panel : Scatterplots with 95 % mean prediction interval. YBOCS, Yale–Brown Obsessive Compulsive Scale ;
AU, arbitrary units.

activations observed between the groups in our study In summary, the current study (although pre-
are therefore a primary effect of disease or of a com- liminary) provides an insight into the effect of CBT
pensatory neuronal reorganization. on neuronal activations in OCD patients. The present
Neuronal activations with the last reversal error results also extend current models of neural mech-
across both groups (Fig. 2) are in line with previous anisms of psychotherapy, suggesting that cognitive
findings (Cools et al. 2002 ; Remijnse et al. 2009). The therapy might act in general from a dorsolateral pre-
between-group comparison before therapy replicates frontal cortex-dominated network (DeRubeis et al.
previously reported reduced activations in the orbito- 2008) to cognitively more distant targets such as the
frontal cortex but extends this effect to areas including orbitofrontal cortex and the basal ganglia.
the striatum (Fig. 3) (Chamberlain et al. 2008). In pre-
vious studies (Remijnse et al. 2006) reduced activations
in the striatum have been restricted to reward feed- Acknowledgments
back or to activations with a planning task (van den This study was supported by a grant from the German
Heuvel et al. 2005). It is interesting to note that the Research Foundation (DFG), Grant VO 542/5-2.
activated areas in the orbitofrontal cortex in our
study are more posterior than those reported pre-
viously (Chamberlain et al. 2008). We hypothesize Declaration of Interest
that differences in task design, for example the use of
None.
abstract patterns or the inclusion of baseline stimuli
(for which the correct response was known in ad-
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